Multidrug recognition and Multidrug transcription activation by the gene regulator, BmrR

Multidrug resistance;Multidrug recogniton;Multidrug signaling;Transcriptional activation;MerR family;Biophysics

Bachas, Sharrol T.Leahy, Daniel J. ;

Johns Hopkins University

关键词: Multidrug resistance;    Multidrug recogniton;    Multidrug signaling;    Transcriptional activation;    MerR family;    Biophysics;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/37156/BACHAS-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Multidrug resistance (MDR) is conferred by multidrug (MD) transporters and MD-responsive gene regulators. Intriguingly, regulation of MD transporters and gene regulators depend on interactions with numerous unrelated chemical structures. This process is called ;;MD recognition” and is the crucial step that controls the MDR induction. In the past decade, structural studies of MD gene regulators bound to diverse ligands illuminated the process of MD recognition. From these studies, two mechanisms of MD recognition were proposed. Although different, these mechanisms demonstrate the general features that govern MD recognition. However, how MDR proteins are regulated by MD recognition remains a mystery. In this dissertation, connect MD recognition and MD signaling by combining results from structural and biochemical studies on the MD gene regulator, BmrR. We identified novel principles that explain how BmrR recognizes and efficiently responds to unrelated drugs. We believe these principles are adopted by other MDR proteins.In chapter 1, we survey the MD recognition properties of various MDR-associated gene regulators whose structures have been determined. In addition, we discuss how the properties of MD recognition pockets contribute to multispecificity. In Chapter 2, we describe the structural basis of MD recognition by BmrR. We define a novel mechanism of MD recognition termed the ;;alternative model”. In addition, we discuss unusual drug-binding modes and discuss their physiological consequences. Finally, we extend our to uncharacterized MDR proteins. Currently, the mechanism of signaling by BmrR and other MDR proteins is still speculative. We have conducted in vitro transcription studies on BmrR response to determine how ligand properties control MD signaling by BmrR. In Chapter 3, we discuss the importance of cationic selectivity in BmrR signaling. In addition, we discuss an uncoupled response mechanism that provides efficient MD responses to dissimilar xenobiotics. In Chapter 4, we explore the mechanism of gene activation by BmrR. We present preliminary results on the effects of inducers and non-inducers on BmrR promoter recognition. Furthermore, we analyze how inducers and non-inducers affect DNA binding and RNA polymerase recruitment. Finally, we analyze the role of ligand-induced promoter bending and DNA distortion in transcription activation by BmrR.